Osteogenesis Imperfecta (O.I.) is a heterogeneous group of diseases in Man showing the common feature of easy fractures of bone. Recent evaluation of clinical, radio-logical, and morphological data have allowed classification of these diseases into four major classes. However, biochemical studies of the molecular defects in Osteogenesis Imperfecta have been sporadic and not closely correlated with the disase manifestations. We have had the opportunity to perform biochemical studies on seven individuals with 2 varieties of O.I. All seven of these patients show collagen-related abnormalities. Six patients classified as Type II O.I. - The broad-bone lethal variety - demonstrate an inability to accumulate Type I collagen into their bone matrices. Another individual, one with multiple fractures and bent bones, but not otherwise easily classified in the current scheme, we have shown to have a severe deficiency of hydroxylysine in bone and a reduced, but significant deficiency of hydroxylysine in cartilage. We propose to study Type II O.I. patients to determine the defect in Type I collagen metabolism responsible for the failure of the bony matrix to accumulate Type I collagen. In addition, we intend to examine the structural and biosynthetic parameters of the collagens present in the connective tissues of other individuals diagnosed to have various other types of Osteogenesis Imperfecta. These studies are directed toward elucidation of the basic molecular defects and a better correlation of defective collagen metabolism with the clinical manifestations. The results of these studies will directly aid genetic counseling of the Osteogenesis Imperfecta individual, as well as provide information regarding the physiological significance of the presence of multiple collagen types within different tissues, and of the multiple posttranslational modifications required for the synthesis of a physiologically competent collagen fiber.